Alternative titles; symbols
SNOMEDCT: 7720002; ORPHA: 175; DO: 14773;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9p13.3 | Cartilage-hair hypoplasia | 250250 | Autosomal recessive | 3 | RMRP | 157660 |
A number sign (#) is used with this entry because cartilage-hair hypoplasia (CHH) is caused by homozygous or compound heterozygous mutation in the RMRP gene (157660) on chromosome 9p13.
Cartilage-hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by short-limbed short stature and fine, sparse hair. Additional features include ligamentous laxity, defective immunity, hypoplastic anemia, and neuronal dysplasia of the intestine (summary by Ridanpaa et al., 2001). CHH was first recognized by McKusick et al. (1965) in the Old Order Amish, a religious isolate (see also McKusick, 1978), and was later recognized as exceptionally prevalent in the Finnish population (Makitie, 1992).
McKusick et al. (1965) described cartilage-hair hypoplasia in several Amish families. Skeletal features included incomplete extension at the elbows, anterolateral chest deformity like Harrison grooves, genu varum, increased lumbar lordosis, and excessively long fibula distally relative to the tibia. The fingers were usually loose-jointed and the fingernails foreshortened. Radiographic examination showed changes of the type called in the past 'metaphyseal dysostosis.' Skeletal biopsy showed cartilage hypoplasia. The hair was fine, sparse, and light-colored, with an abnormally small caliber on microscopic examination. Many patients with CHH had a major immunologic defect that was manifested, for example, as an unusual susceptibility to chickenpox; 6 cases of fatal varicella pneumonia were noted in the original study. In addition to lymphopenia, some patients had anemia and neutropenia. Malabsorption and/or aganglionic megacolon were found in some patients. Autosomal recessive inheritance seemed quite certain, although penetrance was reduced when dwarfism was taken as the phenotype for ascertainment.
Burgert et al. (1965) described a similar syndrome with dyschondroplasia, aregenerative anemia, and celiac syndrome. Some additional features of CHH, including malabsorption and susceptibility to chickenpox, resembled those of the patients with pancreatic insufficiency and neutropenia reported by Burke et al. (1967), and some of their patients had metaphyseal changes. See also the report of Theodorou and Adams (1963).
Polmar and Pierce (1986) described marked impairment of T-cell function due to an intrinsic defect in cell proliferation in patients with CHH. Since defective proliferation was found also in B cells and fibroblasts, they concluded that the defect in cell proliferation was generalized. Accordingly, proliferation-independent natural killer activity was normal. Although Polmar and Pierce (1986) reported that 'an increased incidence of malignancy was not observed in CHH patients,' others (Francomano, 1984) found increased malignancy, including lymphoma, primary liver carcinoma, and duodenal carcinoma. Skin carcinoma in exposed areas may have been related to the hypopigmentation of the skin. Herpes labialis was extraordinarily severe in some patients and was sometimes accompanied by unusual malignancy of the mouth. The literature on 63 non-Amish cases was summarized by van der Burgt et al. (1991). They concluded that there seemed to be no increased susceptibility to malignancy in persons with CHH. However, Gorlin (1992) referred to a patient treated for Hodgkin disease at the age of about 33 years.
Kaitila and Perheentupa (1980) referred to 33 cases of cartilage-hair hypoplasia in 28 families in Finland.
In Finland, Makitie et al. (1999) reviewed 122 patients with CHH who had been identified in 2 countrywide epidemiologic surveys in 1974 and in 1986. Their parents and unaffected sibs were identified through the Population Register Center and the cohort underwent follow-up for cancer incidence through the Finnish Cancer Registry to the end of 1995. A statistically significant excess risk of cancer was seen among the patients with CHH (standardized incidence ratio 6.9, 95% confidence interval 2.3 to 16), which was mainly attributable to non-Hodgkin lymphoma (standardized incidence ratio 90, 95% confidence interval 18 to 264). In addition, a significant increased risk of basal cell carcinoma was seen (standardized incidence ratio 35, 95% confidence interval 7.2 to 102). The cancer incidence among the sibs and parents did not differ from the average cancer incidence in the Finnish population. The increase in non-Hodgkin lymphoma was thought to be attributable to defective immunity in the CHH patients.
There is a remarkable degree of phenotypic variability in all features of the syndrome. The hair may be seemingly completely unaffected; some patients suffer no apparent immunologic or hematologic defect; Hirschsprung disease of clinically evident severity occurs in a minority. Patients may be relatively tall; at least 1 Amish woman, the daughter of 2 affected persons, was 55 inches tall. She was thought to be unaffected until about age 9 when x-rays showed characteristic changes. At the other end of the spectrum of severity is severe involvement in all aspects of the disorder, including extensive aganglionosis of the bowel leading to early demise. In 1 such patient the fingers showed distal arthrogryposis; stiffness of the interphalangeal joints prevented bending of the fingers, which were characteristically short as well, and there were dimples over the metacarpophalangeal joints (McKusick, 1986). Le Merrer and Maroteaux (1991) illustrated the difficulties in making the diagnosis of CHH in the first years of life.
Makitie and Kaitila (1993) reviewed the clinical manifestations of 108 patients with CHH. They emphasized that in addition to short-limbed dwarfism, hypoplastic hair, and defective immunity, patients also defective erythrogenesis. Six patients had normal hair. Childhood anemia had occurred in 79% of the patients; it was usually mild but was severe in 14 patients. Hirschsprung disease was observed in 8, anal stenosis in 1, and esophageal atresia in 1. Intrafamilial variation, as studied in 16 sibships, was considerable. According to Makitie et al. (1992), macrocytosis accompanied the anemia or occurred independent of the anemia during childhood. The reticulocyte index was always low in relation to the anemia. Anemia, which was most prevalent and severe during infancy, underwent spontaneous remission before adulthood in all patients except 3 infants with fatal hypoplastic anemia. Lymphopenia was present in 62% of 88 patients studied, and neutropenia in 24%. Anemia correlated significantly with the severity of the immunodeficiency and growth failure and the presence of neutropenia. Makitie et al. (1992) found that the stature at birth showed a mean relative length of -3.0 SD. The median adult height was 131.1 cm for 15 males (range, 110.7-149.0 cm) and 122.5 cm (range, 103.7-137.4 cm) for 20 females. Adult height showed no correlation with midparent height.
Makitie et al. (1992) analyzed 149 skeletal radiographic surveys of 82 Finnish patients with CHH. Skeletal age was markedly reduced in 14% of patients. Mild scoliosis was observed in one-fourth of patients. Excessive distal length of the fibula and irregularity and flaring of the ribs at the costochondral junction were noted. Six of 108 patients had malignancy: pulmonary lymphoma leading to death at age 10; intestinal lymphosarcoma with death at age 22; malignant testis tumor (progonoma) removed surgically at the age of 6 months; and skin carcinoma in 3 patients.
Makitie et al. (1995) gave an extensive review of CHH.
Glass and Tifft (1999) reviewed the radiologic changes in CHH in infancy, when clinical findings may be subtle and radiographic changes also elusive. In 4 children under the age of 2 years, they emphasized radiologically and clinically discernible anterior angulation of the entire sternum, a sign not previously described in CHH. The finding was present in a 2-week-old girl who also showed short ribs with anterior flaring. A 5-month-old girl showed widening of the atlantoaxial space on lateral cervical spine radiograph. Two patients showed increased lumbar lordosis.
Makitie et al. (1998) studied lymphocyte subpopulations and proliferative responses in mitogen stimulation in 35 patients with CHH, of whom 31% had an increased incidence of infections the year prior to evaluation. Decreased CD4+ cell count was present in 57% of patients, which led to decreased T-lymphocytes in 52% and subnormal CD4+/CD8+ ratio in 32%. The B-lymphocyte cell count was usually normal. Natural killer cell count was above normal in 40% of patients. The lymphocyte stimulation indices, studied with phytohemagglutinin, Concanavalin A, and pokeweed mitogen, were subnormal in 69%, 69%, and 83% of patients, respectively. Total lymphocytes, T-lymphocytes, CD4+ cells, and pokeweed mitogen stimulation index was inversely correlated with frequency of infection. Makitie et al. (1998) concluded that commonly used parameters of cellular immunity poorly predict the clinical outcome of CHH patients. They suggested that all patients be followed carefully because of the possibility of serious infections and malignancies.
Fryns (2000) stated that he and his colleagues had followed 7 patients with CHH from 5 different families during the previous 25 years in Leuven, Belgium. Two of the patients had splenomegaly, which became evident after the age of 2 years and progressed with clinical signs of hypersplenism and portal hypertension with thrombocytopenia and gastrointestinal bleeding from esophagogastric varices. One patient, aged 18 years, showed complete thrombosis of the portal vein. Liver biopsy was normal.
In a review of primary immunodeficiency diseases due to defects in lymphocytes, based on 141 consecutive patients, Buckley (2000) reported 1 case of CHH.
Upon finding causative mutations in the RMRP gene (e.g., 157660.0009), Bonafe et al. (2002) suggested that a diagnostic tell-tale sign of CHH is cone-shaped epiphyses in the phalanges and that patients with metaphyseal chondrodysplasia with cone-shaped epiphyses, even if they lack the extraskeletal features of CHH, should be considered for the presence of RMRP mutations.
Severe anemia requiring transfusion is seen in approximately 6% of patients with CHH. Williams et al. (2005) reported 12 patients with CHH and severe anemia, defined as hemoglobin less than 3.0 g/dL or a history of repeated red blood cell transfusions. In all but 1 patient, anemia developed before 5 months of age; the remaining patient developed aplastic anemia at 2.5 years of age. Three patients died at ages 2 weeks, 3 months, and 6 months, respectively. Most patients had normocytic anemia, but 2 had macrocytic anemia. Five patients had thrombocytosis. Follow-up of the living patients showed that only 2 patients, a 13-year-old girl and a 40-year-old man, had spontaneous and apparently permanent recovery from anemia. The findings indicated that approximately one-half to two-thirds of CHH patients with severe anemia will require lifelong transfusions or bone marrow transplant. No clinical features, hematologic parameters, or genetic mutations were identified that allowed discrimination between those with permanent anemia and those with spontaneous recovery.
Taskinen et al. (2008) reported the 10-year extended follow-up of a cohort of 123 Finnish CHH patients, previously reported by Makitie et al. (1999). During the total mean follow-up time of 19.2 years, 14 cases of cancer were diagnosed in the CHH cohort (standardized incidence ratio, 7.0): non-Hodgkin lymphoma was the most frequent cancer (9 cases; standardized incidence ratio, 90.2) followed by squamous cell carcinoma (3 cases), leukemia (1 case), and Hodgkin lymphoma (1 case); 1 tumor was not histologically classified. Nine of the 14 cancers were diagnosed in patients less than 45 years of age. In addition, 10 patients had basal cell carcinoma of the skin (standardized incidence ratio, 33.2). The cancer incidence for carriers of the CHH gene mutation (e.g., parents) did not differ from the general population; the incidence of cancer in sibs was slightly increased but was not statistically significant.
McCann et al. (2014) reported a 2.8-year-old girl with CHH who presented with progressive granulomatous skin lesions and was diagnosed with severe T-cell immunodeficiency. She had had short stature (height less than 0.4th percentile) since birth and had fine blond hair; bone radiography appeared normal. Severe T-cell immunodeficiency and persistent Epstein-Barr virus (EBV) viremia were indications for hematopoietic stem cell transplantation (HSCT); while waiting for an unrelated donor, the patient developed an EBV-related diffuse large B-cell lymphoma, which required small bowel resection and treatment with anti-B-cell monoclonal antibody (rituximab). One year after HSCT the patient was well and the skin lesions had markedly receded.
Klemetti et al. (2017) reported a Finnish patient with cartilage-hair hypoplasia whose height Z-score remained in the normal range until puberty, resulting in a delay in diagnosis until age 14 years. Three additional patients with the same genotype from the Finnish Skeletal Dysplasia Register were evaluated, and 2 of the 3 also had mild growth failure (height SD -1.6 at 14 years and -3.0 at 12 years, respectively). Despite the milder phenotype in height, the patients had evidence of significant immunodeficiency: 3 of the 4 patients had recurrent infections, 1 had progressive bronchiectasis, and another died from aggressive B-cell lymphoma.
Based on a questionnaire completed by patients, Holopainen et al. (2019) assessed gynecologic health of women with genetically confirmed CHH. Mean age at the time of the survey was 42.3 years. Mean age at menarche and menopause was 12.7 and 46.1 years, respectively. The mean length of the menstrual cycle was 27 days. Most patients (76%) were using contraception, most commonly condoms. Ten (38%) had been pregnant, with 6 reporting miscarriages and 3 reporting induced pregnancy terminations; 8 had a total of 19 deliveries, all by cesarean delivery. There were no reported pregnancy complications. An abnormal Pap smear was reported in 5 patients, with 1 patient having cervical cancer. Many patients expressed concern about risks during pregnancy and desired prepregnancy counseling.
Levin (1978) characterized a possible variant of CHH. Two sibs and one isolated case, in addition to being shorter than most patients with CHH, had dental abnormalities consisting of microdontia, a single notch in the center of the incisal edge of each permanent incisor, and doubling of the lingual cusps of the lower premolars.
Makitie et al. (2001) demonstrated impaired spermatogenesis in CHH, a previously unrecognized feature. In 11 affected males aged 21 to 49 years, semen analyses were not within normal limits in any, as indicated by low sperm concentration, decreased motility, and/or morphologic changes. None of the 11 patients complained of erectile problems or involuntary infertility. Three had a total of 5 children. Makitie et al. (2001) concluded that the defect in cell proliferation in men with CHH also involves the spermatogenic cells.
Kaitila et al. (1975) and Ochs (1975) reported normal red cell adenosine deaminase (ADA; 608958) in patients with CHH. In a boy with CHH, the son of first-cousin parents, Sanchez-Corona et al. (1990) found a 4-fold increase in red blood cell adenosine deaminase activity.
Toiviainen-Salo et al. (2008) performed a retrospective study of 15 Finnish patients with cartilage-hair hypoplasia, 79% with impaired cell-mediated immunity and 71% with impaired humoral immunity. Eight patients (52%) had bronchiectasis, diagnosed with high-resolution CT scan in 6 patients and by bronchography in 2 patients. The findings ranged from localized mild dilatation of the airways to severe bronchiectasis with saccular airway dilatation. Bronchiectasis progressed during follow-up in 2 patients. Patients with bronchiectasis tended to have more severe growth failure and more often had defective humoral immunity than the general CHH population.
Bailly-Botuha et al. (2008) reported 3 children with CHH who presented with chronic obstructive symptoms and bronchiolar wall thickening on high-resolution CT scan; lung biopsy revealed diffuse dilated lymphoplasmacytic bronchiolitis in all 3 patients. The bronchiolar wall was infiltrated by a lymphocyte sheath with plasma cell differentiation and dispersed secondary follicles. Bronchoalveolar lavage fluid cultures were positive for Hemophilus influenzae in 2 patients, 1 of whom also had Streptococcus pneumoniae, and cultures from the third patient were positive for Klebsiella pneumoniae. All 3 responded well to long-term clarithromycin with improvement of respiratory symptoms and pulmonary function.
Leukocyte interferon might be useful in children with CHH and varicella, judging from the apparent benefit in immunosuppressed children with cancer (Arvin et al., 1982).
Acyclovir could have a useful place in the treatment of varicella in patients with CHH (Dunkle et al., 1991; Gnann, 1994; Wood, 1994), and the use of varicella vaccine (Hardy et al., 1991) for prophylaxis would be worthy of consideration. However, an attenuated live polio vaccine might have risks of severe disease in a patient with CHH.
Reactivation of varicella-zoster virus from latency causes zoster and is common among recipients of hematopoietic cell transplants, e.g., those performed for Hodgkin and non-Hodgkin lymphomas. Hata et al. (2002) found that inactivated varicella vaccine given before hematopoietic cell transplantation and during the first 90 days thereafter reduced the risk of zoster. This finding had possible relevance to the use of inactivated varicella vaccine in CHH.
In the initial study of CHH in the Amish by McKusick et al. (1965), a deficiency of affected members of sibships resulted in a lower than expected segregation ratio. A similar deficiency of affected members was not found in analysis of 83 Finnish families by Makitie (1992). In the Amish series, reduced penetrance was suggested as the most likely mechanism of the deficiency, but after the CHH locus was assigned to proximal 9q and several closely linked polymorphic markers were identified, it became possible to search for reduced penetrance by determining the haplotypes of unaffected sibs in multiplex families. Sulisalo et al. (1994) studied 66 clinically unaffected sibs from Finnish and Amish families and found none to be haploidentical with affected sibs. Thus, reduced penetrance or underdiagnosis of mildly manifesting individuals appeared to be ruled out in both populations.
Sulisalo et al. (1997) initiated a repeat segregation analysis in an extended series of Finnish CHH families and analyzed uniplex families in order to look for cases of uniparental disomy, 1 such case having been observed in a family counseled for prenatal diagnosis. Although segregation analysis of 101 families again failed to give evidence of a statistically significant deficiency of affected members, the study of 54 uniplex families revealed 1 additional patient with CHH and uniparental disomy for chromosome 9. In Finland, therefore, 2 of 54 uniplex families showed CHH as a result of chromosome 9 uniparental disomy.
By linkage analysis, Sulisalo et al. (1993) assigned the CHH gene to chromosome 9, between D9S43 and D9S50 (maximum multipoint lod score = 9.94). Based on strong linkage disequilibrium, the closest marker, D9S50, was thought to be less than 1 cM from the gene. No heterogeneity was observed in 14 Finnish families, and there was no evidence of reduced penetrance. Sulisalo et al. (1995) stated that the CHH gene is on 9p close to D9S163 within an interval of 1.5 cM flanked by D9S165 and D9S50. In a study of 9 families with CHH and no genealogic connections to either Amish or Finns, Sulisalo et al. (1995) found no recombinants between the CHH gene and any of the 3 closest marker loci, suggesting that CHH in these families results from mutation(s) at the same locus as in the Amish and Finnish families.
On 'closer inspection of the pedigrees' reported by Sulisalo et al. (1995), Krawczak (1995) concluded that their power to disclose linkage heterogeneity was limited and that a substantial level of heterogeneity might have gone unnoticed.
Ridanpaa et al. (1995) refined the localization of the CHH gene to 9p13 using in situ hybridization for the localization of markers involved in linkage and linkage disequilibrium analyses. They concluded that CHH is approximately 0.3 cM on the proximal side of the microsatellite marker D9S163. PAX5 (167414) also maps to 9p13 and is located between D9S163 and another microsatellite marker within an interval of no more than 56 kb. The following order was proposed for loci on 9p13: cen--D9S50--CHH--D9S163--PAX5--tel.
Using a positional cloning strategy and mutation analysis, Ridanpaa et al. (2001) showed that mutations in the RMRP gene (e.g., 70A-G, 157660.0001) are responsible for CHH.
Hirose et al. (2006) screened 9 Japanese patients for mutations in the RMRP gene and identified homozygous or compound heterozygous mutations in 6 patients. The authors noted that the 70A-G founder mutation prevalent in Western populations had not been found in Japanese patients, whereas 2 mutations common in Japanese patients, 218G-A (see 157660.0012) and a 17-bp duplication at nucleotide +3 (157660.0014), had not been reported in other populations. Haplotype analysis revealed that the 2 latter mutations were contained within rare distinct haplotypes, indicating the presence of unique founders among Japanese CHH patients. Hirose et al. (2006) observed that none of the Japanese patients they evaluated exhibited all of the skeletal, hair, and immunologic features characteristic of classic CHH.
In 4 Finnish patients with CHH, Klemetti et al. (2017) identified compound heterozygosity for the common 70A-G mutation and a 10-bp duplication (157660.0003) in the RMRP gene. Three of the 4 patients had unusually mild growth failure but evidence of significant immunodeficiency.
Makitie (1992) presented an epidemiologic and genetic study of 107 (46 males and 61 females) CHH patients distributed in 85 families in Finland. Of the 107, 18 had died, 7 before the age of 1 year. The living patients ranged in age from 1 to 51 years (median 21 years). The incidence was estimated to be 1:23,000 live births. Consanguinity was found in 2 families. The geographic distribution of the birthplaces of the patients and their great-grandparents showed accumulation in a small area in western Finland, and regional clusters were seen in other parts of the country as well. Segregation analysis was consistent with recessive inheritance with reduced penetrance, as had been suggested by McKusick et al. (1965).
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